Document Detail


Leptin enhances cholangiocarcinoma cell growth.
MedLine Citation:
PMID:  18701500     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cholangiocarcinoma is a strongly aggressive malignancy with a very poor prognosis. Effective therapeutic strategies are lacking because molecular mechanisms regulating cholangiocarcinoma cell growth are unknown. Furthermore, experimental in vivo animal models useful to study the pathophysiologic mechanisms of malignant cholangiocytes are lacking. Leptin, the hormone regulating caloric homeostasis, which is increased in obese patients, stimulates the growth of several cancers, such as hepatocellular carcinoma. The aim of this study was to define if leptin stimulates cholangiocarcinoma growth. We determined the expression of leptin receptors in normal and malignant human cholangiocytes. Effects on intrahepatic cholangiocarcinoma (HuH-28) cell proliferation, migration, and apoptosis of the in vitro exposure to leptin, together with the intracellular pathways, were then studied. Moreover, cholangiocarcinoma was experimentally induced in obese fa/fa Zucker rats, a genetically established animal species with faulty leptin receptors, and in their littermates by chronic feeding with thioacetamide, a potent carcinogen. After 24 weeks, the effect of leptin on cholangiocarcinoma development and growth was assessed. Normal and malignant human cholangiocytes express leptin receptors. Leptin increased the proliferation and the metastatic potential of cholangiocarcinoma cells in vitro through a signal transducers and activators of transcription 3-dependent activation of extracellular signal-regulated kinase 1/2. Leptin increased the growth and migration, and was antiapoptotic for cholangiocarcinoma cells. Moreover, the loss of leptin function reduced the development and the growth of cholangiocarcinoma. The experimental carcinogenesis model induced by thioacetamide administration is a valid and reproducible method to study cholangiocarcinoma pathobiology. Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of cholangiocarcinoma.
Authors:
Giammarco Fava; Gianfranco Alpini; Chiara Rychlicki; Stefania Saccomanno; Sharon DeMorrow; Luciano Trozzi; Cinzia Candelaresi; Julie Venter; Antonio Di Sario; Marco Marzioni; Italo Bearzi; Shannon Glaser; Domenico Alvaro; Luca Marucci; Heather Francis; Gianluca Svegliati-Baroni; Antonio Benedetti
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  68     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-14     Completed Date:  2008-10-02     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6752-61     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bile Duct Neoplasms / metabolism,  pathology*
Bile Ducts / cytology,  metabolism
Bile Ducts, Intrahepatic / metabolism,  pathology*
Cell Proliferation*
Cholangiocarcinoma / chemically induced,  metabolism,  pathology*
Fluorescent Antibody Technique
Humans
Janus Kinases / metabolism
Leptin / physiology*
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Mitogen-Activated Protein Kinase Kinases / metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Zucker
Receptors, Leptin / metabolism
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor / metabolism
Thioacetamide / pharmacology
Grant Support
ID/Acronym/Agency:
DK062975/DK/NIDDK NIH HHS; DK58411/DK/NIDDK NIH HHS; R01 DK054811/DK/NIDDK NIH HHS; R01 DK054811-06A2/DK/NIDDK NIH HHS; R01 DK054811-07/DK/NIDDK NIH HHS; R01 DK062975/DK/NIDDK NIH HHS; R01 DK062975-03/DK/NIDDK NIH HHS; R01 DK062975-04/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Leptin; 0/Receptors, Leptin; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 075T165X8M/Thioacetamide; EC 2.7.10.2/Janus Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases
Comments/Corrections

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